CN111018767B - Preparation method of D-proline derivative and intermediate thereof - Google Patents
Preparation method of D-proline derivative and intermediate thereof Download PDFInfo
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- CN111018767B CN111018767B CN201911340033.XA CN201911340033A CN111018767B CN 111018767 B CN111018767 B CN 111018767B CN 201911340033 A CN201911340033 A CN 201911340033A CN 111018767 B CN111018767 B CN 111018767B
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
Abstract
The invention discloses a preparation method of a D-proline derivative and an intermediate thereof, and the preparation method of the intermediate (R) -1-methylpyrrolidine-2-formaldehyde comprises the following steps: 1) making 1-methyl-D-proline hydrochloride undergo the process of acyl-chlorination reaction to obtain 1-methyl-D-prolyl chloride, then making it and hydrogen undergo the process of catalytic hydrogenation reaction to obtain intermediate; the preparation method of the D-proline derivative (R, E) -3- (1-methylpyrrolidine-2-yl) acrylic acid comprises the following steps: reacting (R) -1-methylpyrrolidine-2-carbaldehyde with ethoxyformylmethylenetriphenylphosphine or triethyl phosphonoacetate to produce ethyl (R, E) -3- (1-methylpyrrolidine-2-yl) acrylate; hydrolyzing and acidifying to obtain the product; the method can obtain more ideal product yield by a shorter route, simultaneously has lower raw material price and easy separation of intermediate products, and is suitable for industrialized large-scale production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a D-proline derivative (R, E) -3- (1-methylpyrrolidine-2-yl) acrylic acid and an intermediate thereof.
Background
(R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid (formula 1) belongs to a class of D-proline derivatives, and is a key intermediate fragment of an antitumor innovative drug pyrroltinib (Pyrotinib) developed by Henry pharmaceutical company:
regarding the preparation method of the compound of formula 1, there are mainly two methods in the prior art, the first is a preparation method disclosed in patent WO2017186140a1, which uses (R) -1-Boc-2-pyrrolidine methanol as a raw material to prepare the compound of formula 1 by the following four-step reaction:
however, in the raw material (R) -1-Boc-2-pyrrolidine methanol adopted in the patent, a protecting group Boc (tert-butyloxycarbonyl) on nitrogen is needed to ensure that good selectivity is kept in the process of converting alcohol into aldehyde, and for industrial application, the protecting group Boc is expensive and is not beneficial to large-scale production; meanwhile, in the reaction route, the product in the first step is an oily substance which is difficult to separate, column chromatography is needed for elution, time and labor are wasted, the production cost is increased, the production efficiency is reduced, and in addition, the yield is also to be improved.
The second method is a synthesis method of the compound of formula 1 disclosed in patent CN108314639B, which also uses (R) -1-Boc-2-pyrrolidine methanol as raw material, and compared with the first method, the method is to make the methyl group on NH before constructing the double bond, as shown in the following synthesis route:
however, the adopted raw material (R) -1-Boc-2-pyrrolidine methanol needs a protecting group Boc (tert-butyloxycarbonyl) on nitrogen to ensure that good selectivity is kept in the process of converting alcohol into aldehyde, and the protecting group Boc is expensive for industrial application and is not beneficial to large-scale production; meanwhile, the (R) -1-methylpyrrolidine-2-formaldehyde needs to undergo three steps of reaction, and the process is long.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art and provide an improved method for preparing the (R, E) -3- (1-methylpyrrolidine-2-yl) acrylic acid intermediate (namely, (R) -1-methylpyrrolidine-2-formaldehyde), which can obtain a more ideal product yield by a shorter route, and is simultaneously low in raw material price, easy in intermediate product separation and suitable for industrial large-scale production.
The invention also provides a preparation method of the D-proline derivative (R, E) -3- (1-methylpyrrolidine-2-yl) acrylic acid.
In order to solve the technical problems, the invention adopts a technical scheme as follows:
a preparation method of (R) -1-methylpyrrolidine-2-formaldehyde, which comprises the following steps:
(1) carrying out acyl chlorination on 1-methyl-D-proline hydrochloride shown in a formula V to prepare 1-methyl-D-prolyl chloride shown in a formula IV;
(2) carrying out catalytic hydrogenation reaction on the 1-methyl-D-prolyl chloride shown in the formula IV prepared in the step (1) and hydrogen to prepare the (R) -1-methylpyrrolidine-2-formaldehyde shown in the formula III;
according to some preferred aspects of the present invention, in step (1), the temperature of the acid chlorination reaction is 30 to 80 ℃.
According to some preferred aspects of the invention, in the step (1), the acyl chlorination reaction is controlled to be carried out in the presence of a catalyst N, N-dimethylformamide, and the feeding molar ratio of the catalyst N, N-dimethylformamide to the 1-methyl-D-proline hydrochloride represented by the formula V is 0.01-0.05: 1.0.
According to some preferred and specific aspects of the present invention, in step (1), the acylchlorination reaction is carried out in an organic solvent which is a combination of one or more selected from the group consisting of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane and acetonitrile.
According to some specific aspects of the present invention, in step (1), the acid chloride reagent used in the acid chloride reaction is one or more selected from the group consisting of oxalyl chloride, thionyl chloride, isobutyl chloroformate, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, sulfuryl chloride, acetyl chloride and chloroacetyl chloride.
According to some preferred aspects of the invention, in step (1), the feeding molar ratio of the 1-methyl-D-proline hydrochloride represented by the formula I to the acyl chlorination reagent is 1.0: 1.0-1.65.
According to some preferred aspects of the present invention, in the step (2), the catalytic hydrogenation reaction is controlled to be carried out in the presence of sodium acetate. In the invention, the addition of sodium acetate in the catalytic hydrogenation reaction can be beneficial to forward movement of the reaction, and more ideal yield is obtained.
According to some preferred aspects of the invention, in the step (2), the feeding molar ratio of the sodium acetate to the 1-methyl-D-proline hydrochloride represented by the formula V is 1.5-1.75: 1.0.
According to some preferred aspects of the present invention, in the step (2), the catalyst used for the catalytic hydrogenation is a palladium barium sulfate catalyst and/or a palladium carbon catalyst. According to a particular aspect of the invention, the palladium on carbon catalyst is 10% palladium on carbon.
According to some preferred aspects of the present invention, in the step (2), the catalytic hydrogenation reaction is carried out in a benzene-based solvent, which is toluene and/or xylene.
According to some preferred aspects of the present invention, in the step (2), the catalytic hydrogenation reaction is carried out at a reaction temperature of 30 to 60 ℃.
According to some preferred aspects of the present invention, in the step (2), the pressure of hydrogen used for the catalytic hydrogenation reaction is 3 to 5 atmospheres.
The invention provides another technical scheme that: a method for preparing (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid, comprising the steps of:
(a) preparing (R) -1-methylpyrrolidine-2-formaldehyde shown in a formula III by adopting the preparation method of the (R) -1-methylpyrrolidine-2-formaldehyde;
(b) reacting (R) -1-methylpyrrolidine-2-formaldehyde shown in a formula III prepared in the step (a) with carbethoxymethylene triphenylphosphine or triethyl phosphonoacetate to prepare (R, E) -3- (1-methylpyrrolidine-2-yl) ethyl acrylate shown in a formula II;
(c) hydrolyzing the ethyl (R, E) -3- (1-methylpyrrolidin-2-yl) acrylate shown in the formula II prepared in the step (b) under an alkaline condition, and acidifying to prepare the (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid shown in the formula I;
according to some specific aspects of the present invention, in the step (b), the reaction is performed in a combined solvent of one or more selected from the group consisting of dichloromethane, chloroform, 1, 2-dichloroethane, methyl t-butyl ether and 1, 4-dioxane.
According to some specific aspects of the invention, in the step (b), the feeding molar ratio of the (R) -1-methylpyrrolidine-2-formaldehyde shown in the formula III to the carbethoxymethylene triphenylphosphine or the triethyl phosphonoacetate is 1.0: 1.2-1.6.
According to some specific aspects of the invention, in step (b), the reaction temperature of the reaction is 25-35 ℃.
According to some particular aspects of the invention, in step (c), the methods and conditions of the hydrolysis are conventional in the art for such reactions.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention creatively takes the 1-methyl-D-proline hydrochloride shown in the formula V as the starting raw material, realizes the industrial production which can obtain more ideal product yield by a shorter route, simultaneously has lower raw material price (avoids a protecting group Boc group adopted in the prior art), has easy separation of intermediate products and is easier to expand.
Detailed Description
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
In the following, all starting materials are either commercially available or prepared by conventional methods in the art, unless otherwise specified.
The following examples 1-3 provide the following routes for the preparation of compounds of formula I:
example 1
A) Preparation of (R) -1-methylpyrrolidine-2-carbaldehyde (formula III):
dissolving 1-methyl-D-proline hydrochloride (50.0g,0.30mol, formula V) in dichloroethane (400mL), adding DMF (0.6mL) as a catalyst, slowly dropwise adding thionyl chloride (50.0g,0.42mol), reacting at 50 ℃ for 3h, carrying out rotary evaporation and concentration on the reaction solution until the reaction solution is dry to obtain 1-methyl-D-prolineoyl chloride shown in formula IV, adding toluene (300mL), stirring uniformly, transferring to a high-pressure hydrogenation kettle, adding 10% palladium barium sulfate catalyst (3.0g, purchased from alatin reagent), adding sodium acetate (41.0g), introducing hydrogen at 3 atm, reacting at 30 ℃ for 12h, carrying out suction filtration to remove the catalyst through kieselguhr, washing with toluene, carrying out rotary evaporation and concentration on the filtrate until the filtrate is dry to obtain (R) -1-methylpyrrolidine-2-formaldehyde shown in formula III, and a white solid (30.0g), the yield was 88% and the purity was 95.1%.
B) Preparation of ethyl (R, E) -3- (1-methylpyrrolidin-2-yl) acrylate (formula II):
dissolving (R) -1-methylpyrrolidine-2-formaldehyde (30.0g,0.27mol, formula III) in dichloromethane (300mL), dropwise adding a dichloromethane (200mL) solution of carbethoxymethylene triphenylphosphine (120.0g,0.34mol), reacting at 35 ℃ for 3h, after the reaction is finished, carrying out reduced pressure rotary evaporation to dryness, extracting dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing a crude product with an ethyl acetate-petroleum ether mixed solvent to obtain (R, E) -3- (1-methylpyrrolidine-2-yl) ethyl acrylate (formula II), and obtaining a white solid (40.0g), wherein the yield is 82%, and the purity is 98.2%.
C) Preparation of (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid (formula I):
dissolving (R, E) -3- (1-methylpyrrolidin-2-yl) ethyl acrylate (40.0g,0.22mol, formula II) in MeOH/water (3:1, 400mL), adding NaOH (20.0g,0.5mol), reacting at 50 ℃ for 2h, after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid until the reaction liquid is dry, adding diluted hydrochloric acid to adjust the reaction liquid to be neutral, adding ethyl acetate to extract, drying by magnesium sulfate, carrying out reduced pressure rotary evaporation and concentration until the reaction liquid is dry, and recrystallizing the crude product by methanol to obtain (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid shown in the formula I, wherein the white solid (32.0g) is obtained, the yield is 94%, and the purity is 98.4%.
Example 2
A) Preparation of (R) -1-methylpyrrolidine-2-carbaldehyde (formula III):
dissolving 1-methyl-D-proline hydrochloride (80.0g,0.48mol, formula V) in chloroform (700mL), adding DMF (1mL) as a catalyst, slowly dropwise adding oxalyl chloride (98.0g,0.77mol), reacting at 80 ℃ for 1h, carrying out rotary evaporation and concentration until the reaction solution is dry to obtain 1-methyl-D-prolineoyl chloride shown in formula IV, adding xylene (1000mL), stirring uniformly, transferring to a high-pressure hydrogenation kettle, adding 10% palladium-carbon (5.0g, from an alatin reagent), adding sodium acetate (66.0g), introducing hydrogen, reacting at 40 ℃ for 8h under 4 atmospheric pressure, carrying out suction filtration after the reaction is finished, removing the catalyst through kieselguhr, washing the xylene for several times, carrying out rotary evaporation and concentration until the filtrate is dry to obtain (R) -1-methylpyrrolidine-2-formaldehyde shown in formula III, and a white solid (49.0g), the yield was 90% and the purity was 94.9%.
B) Preparation of ethyl (R, E) -3- (1-methylpyrrolidin-2-yl) acrylate (formula II):
(R) -1-methyl pyrrolidine-2-formaldehyde (48.0g,0.42mol, formula III) is dissolved in chloroform (500mL), stirred uniformly, 60% NaH (17.0g) is slowly added, a chloroform (200mL) solution of triethyl phosphonoacetate (115.0g,0.51mol) is added dropwise, reaction is carried out for 12h at 25 ℃, after the reaction is finished, reduced pressure rotary evaporation is carried out till dryness, dichloromethane is extracted, salt water washing is carried out, anhydrous sodium sulfate is dried, reduced pressure rotary evaporation is carried out till dryness, and a crude product is recrystallized by an ethyl acetate-petroleum ether mixed solvent to obtain (R, E) -3- (1-methyl pyrrolidine-2-yl) ethyl acrylate (formula II), white solid (69.0g), yield is 89%, and purity is 98.5%.
C) Preparation of (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid (formula I):
dissolving (R, E) -3- (1-methylpyrrolidin-2-yl) ethyl acrylate (68.0g,0.37mol, formula II) in EtOH/water (3:1, 800mL), adding KOH (50.0g,0.89mol), reacting at 50 ℃ for 2h, after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction liquid until the reaction liquid is dry, adding diluted hydrochloric acid to adjust the reaction liquid to be neutral, adding ethyl acetate to extract, drying by magnesium sulfate, carrying out reduced pressure rotary evaporation and concentration until the reaction liquid is dry, and recrystallizing the crude product by methanol to obtain (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid shown in the formula I, wherein the white solid (53.0g) is obtained, the yield is 92%, and the purity is 98.4%.
Example 3
A) Preparation of (R) -1-methylpyrrolidine-2-carbaldehyde (formula III):
dissolving 1-methyl-D-proline hydrochloride (28.0g,0.17mol, formula V) in methyl tert-butyl ether (250mL), adding DMF (0.4mL) as a catalyst, slowly dropwise adding phosphorus oxychloride (26.5g,0.17mol), reacting at 30 ℃ for 5h, carrying out rotary evaporation and concentration on the reaction solution until the reaction solution is dried to obtain 1-methyl-D-prolineoyl chloride shown in formula IV, adding toluene (380mL), stirring uniformly, transferring to a high-pressure hydrogenation kettle, adding 10% palladium barium sulfate catalyst (1.8g, purchased from alatin reagent), adding sodium acetate (23.0g), introducing hydrogen at 5 atm, reacting at 60 ℃ for 4h, carrying out suction filtration, removing the catalyst through kieselguhr, washing for several times, carrying out rotary evaporation and concentration on the filtrate until the filtrate is dried to obtain (R) -1-methylpyrrolidine-2-formaldehyde shown in formula III, and white solid (17.0g), the yield was 89%, and the purity was 95.0%.
B) Preparation of ethyl (R, E) -3- (1-methylpyrrolidin-2-yl) acrylate (formula II):
(R) -1-methyl pyrrolidine-2-formaldehyde (15.0g,0.13mol, formula III) is dissolved in 1, 2-dichloroethane (190mL), a solution of carbethoxymethylene triphenylphosphine (72.5g,0.21mol) in 1, 2-dichloroethane (120mL) is added dropwise, the reaction is carried out for 7h at 30 ℃, after the reaction is finished, reduced pressure rotary evaporation is carried out till dryness, dichloromethane is extracted, salt water washing is carried out, anhydrous sodium sulfate is dried, reduced pressure rotary evaporation is carried out till dryness, the crude product is recrystallized by an ethyl acetate-petroleum ether mixed solvent to obtain (R, E) -3- (1-methyl pyrrolidine-2-yl) ethyl acrylate (formula II), a white solid (20.5g), the yield is 84%, and the purity is 98.4%.
C) Preparation of (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid (formula I):
dissolving (R, E) -3- (1-methylpyrrolidin-2-yl) ethyl acrylate (20.0g,0.11mol, formula II) in isopropanol/water (3:1, 250mL), adding NaOH (13.0g,0.33mol), reacting at 45 ℃ for 2.5 hours, reducing pressure and carrying out rotary evaporation on the reaction liquid until the reaction liquid is dry, adding diluted hydrochloric acid to adjust the reaction liquid to be neutral, adding ethyl acetate for extraction, drying by magnesium sulfate, reducing pressure and carrying out rotary evaporation and concentration until the reaction liquid is dry, and recrystallizing the crude product by methanol to obtain the (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid shown in the formula I, wherein the white solid (16.0g) is obtained, the yield is 94%, and the purity is 98.8%.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (4)
1. A preparation method of (R) -1-methylpyrrolidine-2-formaldehyde, which is characterized by comprising the following steps:
(1) carrying out acyl chlorination on 1-methyl-D-proline hydrochloride shown in a formula V to prepare 1-methyl-D-prolyl chloride shown in a formula IV; the temperature of the acyl chlorination reaction is 30-80 ℃, the acyl chlorination reaction is controlled to be carried out in the presence of a catalyst N, N-dimethylformamide, and the feeding molar ratio of the catalyst N, N-dimethylformamide to the 1-methyl-D-proline hydrochloride shown in the formula V is 0.01-0.05: 1.0; the acyl chlorination reagent adopted in the acyl chlorination reaction is one or a combination of more of oxalyl chloride, thionyl chloride, isobutyl chloroformate, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, sulfuryl chloride, acetyl chloride and chloroacetyl chloride, and the feeding molar ratio of the 1-methyl-D-proline hydrochloride shown in the formula V to the acyl chlorination reagent is 1.0: 1.0-1.65;
(2) carrying out catalytic hydrogenation reaction on the 1-methyl-D-prolyl chloride shown in the formula IV prepared in the step (1) and hydrogen to prepare the (R) -1-methylpyrrolidine-2-formaldehyde shown in the formula III; controlling the catalytic hydrogenation reaction to be carried out in the presence of sodium acetate, wherein the catalyst adopted by the catalytic hydrogenation is a palladium barium sulfate catalyst and/or a palladium carbon catalyst, the catalytic hydrogenation reaction is carried out at the reaction temperature of 30-60 ℃, and the pressure of hydrogen adopted by the catalytic hydrogenation reaction is 3-5 atmospheric pressures;
2. the process for producing (R) -1-methylpyrrolidine-2-carbaldehyde according to claim 1, wherein in the step (1), the acid chlorination reaction is carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, methyl t-butyl ether, 1, 4-dioxane and acetonitrile.
3. The process for producing (R) -1-methylpyrrolidine-2-carbaldehyde according to claim 1, wherein in the step (2), the catalytic hydrogenation is carried out in a benzene-based solvent which is toluene and/or xylene.
4. A method for producing (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid, comprising the steps of:
(a) (R) -1-methylpyrrolidine-2-carbaldehyde represented by the formula III is produced by the production method of (R) -1-methylpyrrolidine-2-carbaldehyde described in any one of claims 1 to 3;
(b) reacting (R) -1-methylpyrrolidine-2-formaldehyde shown in a formula III prepared in the step (a) with carbethoxymethylene triphenylphosphine or triethyl phosphonoacetate to prepare (R, E) -3- (1-methylpyrrolidine-2-yl) ethyl acrylate shown in a formula II;
(c) hydrolyzing the ethyl (R, E) -3- (1-methylpyrrolidin-2-yl) acrylate shown in the formula II prepared in the step (b) under an alkaline condition, and acidifying to prepare the (R, E) -3- (1-methylpyrrolidin-2-yl) acrylic acid shown in the formula I;
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| CN114507173A (en) * | 2022-03-08 | 2022-05-17 | 重庆医药高等专科学校 | Preparation method of 1-methylpyrrolidine-2-acrylic acid hydrochloride |
| CN114736146A (en) * | 2022-03-17 | 2022-07-12 | 重庆医药高等专科学校 | Preparation method of novel 1-methylpyrrolidine-2-acrylic acid |
| CN114890930A (en) * | 2022-04-18 | 2022-08-12 | 重庆医药高等专科学校 | Synthesis method of pyrroltinib intermediate (R, E) -3- (1-methylpyrrolidine-2-yl) acrylic acid hydrochloride |
| CN114874118A (en) * | 2022-04-18 | 2022-08-09 | 重庆医药高等专科学校 | Method for synthesizing N-methyl-D-prolinol by one-pot method |
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